Bibliographic details of references provided in the subject specification are listed at the end of the specification.
Reference to any prior art is not, and should not be taken as an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
Interleukin-11 (IL-11) is a member of the IL-6 family of cytokines which includes IL-6, viral IL-6 (vIL-6), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neutrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine/cytokine-like factor-1 (CLC/CLF), IL-27 and neuropoietin (NP). IL-11 is able to stimulate the growth and differentiation of various lineages of hematopoietic cells, either alone or in synergy with other cytokines. IL-11 is also able to stimulate megakaryopoiesis and platelet production, and is used clinically to prevent chemotherapy-induced thrombocytopenia (Tepler et al, Blood 87(9):3607-3614, 1996) and is currently being assessed as a new approach to the treatment of chemotherapy-induced gastrointestinal mucositis (Herrlinger et al, Am J Gastroenterol 101(4):793-797, 2006). IL-11 has also been suggested as being of benefit in arthritis and inflammatory bowel disease.
IL-11 also exerts a variety, of biological activities outside the hematopoietic system. It is a regulator of osteoclast development and believed to be a regulator of bone metabolism (Girasole et al, J clin Invest 93:1516-1524, 1994; Hughes et al, Calcif tissue Int 53:362-364, 1993; Heymann and Rousselle, Cytokine 12(10):1455-1468, 2000). IL-11 is expressed at high levels in cells of the CNS (Du et al, J Cell Physiol 168:362-372, 1996) and stimulates the survival and proliferation of neuronal progenitor cells (Mehler et al, nature 362:62-65, 1993). In female mice, IL-11 is essential for successful embryo implantation (Dimitriadeis et al, Mol Hum Reprod. 6(10):907-914, 2000; Robb et al, Nat Med 4:303-308, 1998; Bilinski et al, Genes Dev 12:2234-2243, 1998) and the expression pattern of IL-11 and its receptors during the menstrual cycle suggests a similar role in humans. Other non-hematopoietic activities of IL-11 include inhibition of adipogenesis (Ohsumi et al, FEBS Lett 288:13-16, 1991; Ohsumi et al, Biochem Mol Biol Int 32:705-712, 1994), induction of a febrile response (Lopez-Valpuesta et al, Neruopharmacology 33:989-994, 1994), modulation of extracellular matrix metabolism (Maier et al, J Biol chem. 268:21527-21532, 1993), stimulation of acute-phase reactants (Baumann and Schendel, J Biol Chem 266:20424020427 1991), and proposed pro- and anti-inflammatory roles (Trepicchio et al, J Clin Invest 104:1527-1537, 1999; Redlich et al, J Immunol 157:1705-1710, 1996).
IL-11 has also been suggested as a potential therapeutic agent in various other inflammatory disorders including radiation-induced lung damage (Redlich et al, supra 1996), sepsis (Chang et al, Blood Cells Mol Dis 22(1):57-67, 1996) and psoriasis (Trepicchio et al, supra 1999). U.S. Pat. No. 6,270,759 suggests that IL-11 may be therapeutically useful for a variety of inflammatory conditions including asthma and rhinitis.
Indicative of the therapeutic interest in IL-11, US Patent Application No. 2007/0190024 describes modified forms of IL-11 with mutations at His 182 (H182) and Asp 186 (D186) which act as agonists and hyperagonists of IL-11.
IL-11 exerts its effects via association with a specific cell surface receptor (IL-11Rα) as well as the shared receptor subunit gp130. While all IL-6 family cytokines signal through receptor complexes involving one or more gp130 molecules, the IL-11 signaling complex is most similar to that of IL-6 in that it comprises two molecules each of the cytokine, specific α-chain receptor and gp130 (Barton et al, J Biol Chem (2000) 275:36197-36203, 2000).
While neutralizing antibodies and soluble receptor proteins are a common strategy for inhibiting cytokines, a third class of antagonist molecules are referred to as “cytokine muteins” which prevent signaling by binding to only one of the two receptor chains. A number of these muteins has previously been described and one, an antagonistic variant of growth hormone, is used clinically to treat acromegaly (Cunningham and Wells, Science 244:1081-1085, 1989). Within the IL-6 family of cytokines, cytokine muteins have been described for IL-6, CNTF, LIF and IL-11 (Ehlers et al, J Biol Chem 270:8158-8163, 1995; Brakenhoff et al, J Biol Chem 269:86-93, 1994; Savino et al, Embo J 13:5863-5870, 1994; Hudson et al, J Biol Chem 271:11971-11978, 1996; Saggio et al, Embo J 14; 3045-3054, 1995; Underhill-Day et al, Endocrinology 144; 3406-3414, 2003). In each case, these cytokine mutein contain specific mutations which prevent binding of cytokine to gp130. In the case of IL-11, a single point mutation, W147A (a tryptophan to alanine substitution at amino acid residue 147), is sufficient to convert IL-11 from an agonist into an antagonist of IL-11 signaling with the affinity for IL-11Rα unchanged (Underhill-Day et al, supra 2003).
In addition, structure-function studies have identified various regions of murine and human IL-11 which are important for IL-11Rα binding (Czupryn et al, J. Biol. Chem. 270 (2): 978-985, 1995; Miyadai et al, Biosci. Biotechnol. Biochem. 60.3:541-542, 1996; Czupryn et al, Ann. N.Y. Acad. Sci. 762:152-164, 1995; Tacken et al, Eur. J. Biochem. 265.2:645-655, 1999; Harmegnies et al, Biochem J. 375(1):23-32, 2003). In particular, residues D165, W166, R169, L172 and L173 at the C-terminal end of the D-helix, and M58, L64 and L67 in the A-B loop were found to contribute to IL-11Rα binding.
US Patent Application No. 2007/0190024 describes IL-11 muteins with mutations at His 182 (H182) and Asp 186 (D186) of IL-11 as agonists and hyperagonists of IL-11, but does not suggest antagonists. The IL-11 mutein, W147A IL-11, is an antagonistic variant of IL-11 that prevents the recruitment of gp130 to the IL-11 receptor complex (Underhill-Day et al, supra 2003) thereby preventing IL-11 signaling. However, W147A IL-11 has the same affinity for IL-11Rα as wild-type IL-11.
There is a role for IL-11 modulators in therapy. The identification of further IL-11 modulators is required.